P1049: A PHASE 2 STUDY OF BEZUCLASTINIB (CGT9486), A NOVEL, HIGHLY SELECTIVE, POTENT KIT D816V INHIBITOR, IN ADULTS WITH ADVANCED SYSTEMIC MASTOCYTOSIS (APEX): METHODS, BASELINE DATA, AND EARLY INSIGHTS
Authors: D. J. DeAngelo, V. Pullarkat, M. Piris-Villaespesa, T. I. George, J. L. Patel, C. Ustun, P. Bose, M. L. Heaney, A. Pilla, M. Massaro, B. Exter, H. A. Jolin, Z. Mikhak, T. Tashi
Journal: HemaSphere (2022)

Background: Systemic mastocytosis (SM) is a rare disease characterized by accumulation of pathogenic mast cells in bone marrow and extracutaneous tissues with or without skin involvement. In approximately 95% of adult patients, SM pathogenesis is driven by a gain-of-function mutation (D816V) in exon 17 of the KIT gene. Advanced systemic mastocytosis (AdvSM) is an aggressive, life-threatening form of SM with three variants: aggressive systemic mastocytosis (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Overall survival ranges from <6 months to 3-4 years. Bezuclastinib (CGT9486) is an orally administered, highly selective and potent tyrosine kinase inhibitor (TKI) that targets KIT D816V, avoiding other closely related kinases with clinical liabilities such as PDGFRα, PDGFRβ, and CSF1R. Bezuclastinib has demonstrated low brain penetration in preclinical tissue distribution studies, potentially addressing challenges associated with other targeted agents such as CNS effects and intracranial hemorrhage. Bezuclastinib has been administered to >100 participants in clinical trials, including 51 patients with advanced solid tumors (e.g., GIST) in a Phase 1b/2a study. In that study, bezuclastinib led to a reduction in KIT exon 17 mutational burden, temporally correlated with a reduction in tumor burden, and an acceptable safety profile. Aims: To describe the Apex study methods and present baseline data and preliminary findings from Part 1 of this Phase 2 clinical trial evaluating bezuclastinib in patients with AdvSM (NCT04996875). Methods: This open-label, 2-part, multicenter study aims to enroll approximately 140 adult patients with AdvSM per WHO criteria assessed with SM-related organ damage and baseline serum tryptase of ≥20 ng/mL. Part 1 patients are randomized 1:1:1:1 to 50, 100, or 200 mg of bezuclastinib twice daily, or 400 mg once daily. Data from Part 1 will help determine the optimal dose of bezuclastinib, which will be utilized to further assess safety, efficacy, PK, and PD in Part 2. The primary efficacy endpoint is overall response rate (% patients classified as confirmed responders; CR, CRh, PR and CI) according to mIWG-MRT-ECNM response criteria, assessed by a Central Response Review Committee. Results: Patients diagnosed with ASM, SM-AHN, and MCL have been enrolled in Part 1 (dose optimization) at centers in Europe and the United States. Baseline values include median (min, max) serum tryptase of 170 ng/mL (95.7-303), KIT D816V variant allele fraction 8.7% (7.04-13.48) by ddPCR, and bone marrow mast cells of 70% (7-80) by IHC. Dosing continues in these patients and the study is actively enrolling. Preliminary safety, PK, and PD data from Part 1 will be presented. Safety data will include AEs/SAEs/AECIs and dose modification frequencies while PD biomarker data, as early evidence of target engagement and clinical activity, will include changes in mast cell and KIT D816V mutational burden. Summary/Conclusion: There is a significant unmet need for novel, safe, and effective treatment options for patients with AdvSM. Bezuclastinib, an orally administered and highly selective TKI with potent activity against KIT D816V, may be a treatment option in AdvSM. Part 1 of the Apex study aims to determine the optimal dose to further evaluate in Part 2. Early insights into the safety and tolerability profile and biomarker data will further inform clinical development of bezuclastinib in AdvSM.